Abstract
SummaryThe functions of Nr4a1-dependent Ly6Clow monocytes remain enigmatic. We show that they are enriched within capillaries and scavenge microparticles from their lumenal side in a steady state. In the kidney cortex, perturbation of homeostasis by a TLR7-dependent nucleic acid “danger” signal, which may signify viral infection or local cell death, triggers Gαi-dependent intravascular retention of Ly6Clow monocytes by the endothelium. Then, monocytes recruit neutrophils in a TLR7-dependent manner to mediate focal necrosis of endothelial cells, whereas the monocytes remove cellular debris. Prevention of Ly6Clow monocyte development, crawling, or retention in Nr4a1−/−, Itgal−/−, and Tlr7host−/−BM+/+ and Cx3cr1−/− mice, respectively, abolished neutrophil recruitment and endothelial killing. Prevention of neutrophil recruitment in Tlr7host+/+BM−/− mice or by neutrophil depletion also abolished endothelial cell necrosis. Therefore, Ly6Clow monocytes are intravascular housekeepers that orchestrate the necrosis by neutrophils of endothelial cells that signal a local threat sensed via TLR7 followed by the in situ phagocytosis of cellular debris.
Highlights
Monocytes are a heterogeneous population of blood phagocytic leucocytes that differentiate in the bone marrow
CX3CR1high CD11b+ Ly6Clow Monocytes Are Enriched in the Microvasculature of the Skin and Kidney in a Steady State Monocytes that adhere to the lumenal side of the endothelium of dermal and heart capillaries, cremaster, mesenteric vessels, and glomeruli in the steady state have been identified by intravital microscopy as CX3CR1high CD11b+ F4/80+ leucocytes (Auffray et al, 2007; Hanna et al, 2011; Li et al, 2012; Sumagin et al, 2010; Devi et al, 2013)
Crawling CD11b+ CX3CR1high monocytes are present in the vascular network that ramifies around renal tubules in the kidney cortex (Figures 1A and 1B; Movie S1 available online)
Summary
Monocytes are a heterogeneous population of blood phagocytic leucocytes that differentiate in the bone marrow. Ly6C+ monocytes exit the bone marrow and extravasate into peripheral inflamed tissues, partly in response to chemokines that signal via C-C chemokine receptor type 2 (CCR2) (Serbina and Pamer, 2006; Tsou et al, 2007) They differentiate into inflammatory macrophages and dendritic cells (DCs) that produce tumor necrosis factor (TNF), inducible nitric oxide synthase, and reactive oxygen species in response to bacterial and parasitic infection (Narni-Mancinelli et al, 2011; Robben et al, 2005; Serbina and Pamer, 2006; Serbina et al, 2003b) and can stimulate naive T cells (Geissmann et al, 2003; Serbina et al, 2003a). It is believed that Ly6C+ monocytes play a role in chronic inflammation, such as the formation of the atherosclerotic plaque, because Ccr2-deficient mice on low density lipoprotein receptor- or apolipoprotein E-deficient backgrounds and a highfat diet have decreased atherosclerosis (Boring et al, 1998; Dawson et al, 1999)
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